Medical Genetics 2

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Medical Genetics 2

• Prof Duncan Shaw

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Risk calculations

• In genetic counselling, we want accurate risk
  assessment for families with genetic disease
• What kinds of information can be used?
• Pedigree
• Biochemical
• DNA
• Using X-linked recessive inheritance as an
  example

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X-linked recessive inheritance

• Usually affects males
• Usually born to asymptomatic carrier mothers who
  may have other affected male relatives
• Females may be affected if the father affected
  and mother a carrier
• Females may be affected due to non-random X
  inactivation
• No male to male transmission

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Duchenne Muscular Dystrophy

• DMD is a relatively common (1/3000 births) and
  fatal genetic disorder
• Major symptom is progressive muscle weakness
• Incurable
• Affected boys are in wheelchairs by age 10-12,
  and die by early 20s of heart or respiratory
  failure
• Caused by mutation in the dystrophin gene on Xp21

From USA Muscular Dystrophy Association
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Dystrophin
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Genetics of DMD

• 1/3 of DMD cases are new mutations (so no LD)
• 2/3 have carrier mothers, 1/3 of which are new
  mutations themselves
• About 60 of mutations are deletions
• DMD is a big gene over 2Mb
• Other mutations in this gene cause a milder
  phenotype - Becker Muscular Dystrophy (BMD)

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A DMD pedigree

• II 1 had brothers with DMD
• She has 4 healthy sons
• Is she a carrier?

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Evidence for carrier risk calculation

• Pedigree evidence - her mother is a carrier so
  her prior risk is 50 - but has 4 healthy sons
• Biochemical evidence - because of X inactivation
  some muscle cells have mutant X active and
  release creatine kinase (CK) so 2/3 carrier
  females have increased CK levels
• DNA evidence
• Deletions of the DMD gene could be tested for
  (60 of DMD caused by deletion mutations)
• Linked markers
• None of the above is necessarily definitive

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Bayesian calculation
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Biochemical evidence

• Creatine kinase in normal women and DMD carriers

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Bayesian calculation (2)
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DNA evidence

• 60 of DMD mutations are deletions easy to
  detect by DNA analysis
• If we dont have DNA from the affected family
  members, cant be sure if mutation in family is a
  deletion
• So if we test the DNA and it isnt deleted, there
  could still be a DMD mutation (such as a
  frame-shift)

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Bayesian calculation (3)
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Using linked markers

• If you dont know what the mutation is (or even
  what the disease gene is) but have closely linked
  markers, can use these to modify risk
• Marker shown is linked to disease with 5
  recombination
• Mother has not received the same allele as
  affected brothers

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Bayesian calculation (4)